1. Field of the Invention
The invention relates to a combination of testosterone and testosterone esters (or to the sole use of testosterone esters) in a buccal, bioadhesive preparation so that, by finely adjusted dosing of the active ingredients and ester selection, various desired plasma levels of testosterone can be set or produced in individual patients, for example to restore an endogenous body rhythm.
2. Description of the Related Art
Testosterone is quantitatively and qualitatively the most important androgen synthesized in the body. It is formed mainly in the testicles and in small amounts in the adrenal glands and in women in the ovaries. In males, testosterone is responsible for the development of the male characteristics during fetal, neonatal and pubertal maturation and finally for attaining the male phenotype and for androgen-dependent functions (for example spermatogenesis). Testosterone exerts protein-anabolic action (in muscles, bones, hematopoiesis, kidneys and liver) {E. Mutschler, “Arzneimittelwirkungen” [Drug Actions], 6th edition, pp. 334–337, Wissenschaftliche Verlagsgesellschaft mbh [publisher], Stuttgart, 1991}.
After oral or parenteral administration, testosterone is rapidly absorbed in the gastrointestinal tract. It is then transported by the portal vein to the liver where it is rapidly metabolized. As a result, the plasma half-life of testosterone is short, i.e., about 10 minutes {Auterhoff, H., Knabe, J. and Höltje, H. D., “Lehrbuch der Pharmazeutischen Chemie” [Textbook of Pharmaceutical Chemistry], 12th edition, pp. 570–573, Wissenschaftliche Verlagsgesellschaft mbh [publisher], Stuttgart, 1991}. To develop a physiological serum level, oral administration of 400 mg (!) of testosterone is needed (S. G. Johnson, E. P. Bennet and V. G. Jensen, Therapeutic effectiveness of oral testosterone, Lancet 2:1974, 1473–1475).
To prolong the action of testosterone, testosterone esters with varying chain length (testosterone propionate, testosterone enantate, testosterone undecanoate) are injected intramuscularly as an oily solution or suspension. It is known that in contact with body fluids these esters will slowly hydrolyze under the action of esterases thus releasing the pharmacologically active testosterone. The influence of the type of ester on the growth of the capon comb after i.m. injection has already been described (Meier, R. and Tschopp, E., Arch. Exptl. Pathol. Pharmacol. 226:1955, 532).
Moreover, testosterone undecanoate (in oleic acid, as a soft gelatin capsule) is administered orally via the lymphatic route [Andriol® preparation]. From the oleic acid-embedded preparation, the drug passes from the gastrointestinal tract through the thoracic duct into the lymph tract thus reaching the systemic circulation. This gives rise to varying serum levels and gastrointestinal side effects. These effects can make long-term replacement therapy difficult (A. M. Matsumoto: Hormonal therapy of male hypogonadism, Endocrinol. Metab. Clin. North Am. 23:1994, 857–875).
Other routes of administration (transdermal, nasal, sublingual, buccal, subcutaneous) have been studied by various research groups (for example, by N. A. Mazer, W. E. Heiber, J. F. Moellmer, A. W. Meikle, J. D. Stringham, S. W. Sanders, K. G. Tolman and W. D. Odell, Enhanced transdermal delivery of testosterone: A new physiological approach for androgen replacement in hypogonadal men, J. Controll. Rel. 19:1992, 347–362).
Drawbacks of the aforesaid therapies are: 1. either a too short, rapidly decreasing testosterone level (after oral administration) or 2.—in the case of intramuscular injection of testosterone esters—the fact that a constantly set testosterone level cannot be changed over a long period of time (days to weeks) thus not allowing individual time control of the testosterone action. Moreover, down regulation of the basal testosterone secretion can take place.
The low bioavailability caused by the high first-pass effect in the liver can be circumvented by buccal or sublingual administration. Various studies confirm this (for example, Pitha, J., Anaissie, J. and Uekama, K., g-Cyclodextrin: Testosterone complex suitable for sublingual administration, J. Pharmaceutical Sciences 76 (10):1987, 788–790).
Buccal administration of drugs is known from the prior art.
EP-0371466 A concerns a rapidly soluble tablet for fast buccal administration of steroids, among other things (for example estrogens, progestins). The main ingredient used is a water-soluble polyhydric alcohol, particularly sorbitol. The advantage is a rapid initial increase in drug concentration.
EP-0286581 A discloses the transmucosal buccal administration of estrogens (17β-estradiol and ethinylestradiol). The estrogen is used within the framework of hormone replacement therapy in postmenopausal women for treating PMS (postmenopausal syndrome) and for osteoporosis therapy at a dose of 50–100 μg/day (17β-estradiol for PMS therapy) and at a dose of 200–400 μg/day (17β-estradiol for osteoporosis therapy). Buccal administration makes it possible to attain therapeutic plasma levels by circumventing the first-pass effect.
WO-704342 describes a special formulation said to be particularly suitable for, among other things, the buccal administration of estrogens (for example estradiol and the esters of estradiol), progestins, androgens and anabolic steroids. This formulation contains a) about 1–20% of a soluble, adhesive polymer (carbomers, partly hydrolyzed polyvinyl alcohol [PVA], polyethylene oxide, polyacrylate, hydroxypropylmethylcellulose), b) a soluble, directly tabletted auxiliary agent and c) the active ingredient. The adhesive polymer makes the formulation or drug form adhere at the site of administration.
U.S. Pat. No. 4,396,615-A describes the treatment of androgen-related diseases by administration of 6-methylene-progesterone, a testosterone-5α-reductase inhibitor, in the form of topical formulations. Such formulations contain the inhibitor and an inert topical carrier (for example, a silicone, methylcellulose, hydroxymethylcellulose).
CA-2105887-A discloses a bioerodable system for buccal and vaginal administration of hormones (estradiol), among other things. The system is water-soluble and mucoadherent. It consists of a solid, soluble, lyophilized foam and the active ingredient. The disintegration time is at least 8 hours. The system adheres to the mucosal membrane where it releases the drug. The polymers used are primarily gelatin, sodium carboxymethylcellulose, methylcellulose etc. A particular advantage of the system is its long adhesion time.
As regards the tailored time-release control of drugs, note that it is not possible for our currently available drugs to provide variable release of the active ingredient nor to adapt the release to the drug needs of an individual patient.
For release-control purposes, current depot drugs use passive dissolution, diffusion, swelling and erosion processes {Gröning, R., “Arzneiformen mit elektronisch gesteuerter Freisetzung” [Drug Forms with Electronically Controlled Release], in “Pharmazeutische Technologie: Moderne Arzneiformen” [Pharmaceutical Technology: Modern Drug Forms], p. 441, ed. [sic-Translator], Müller R. H. and Hildebrand, G. E. (editors), Wissenschaftliche Verlagsgesellschaft mbh [publisher], Stuttgart, 1998}.
The time-controlled release of drugs is also known from the prior art.
JP-07118143 discloses time-controlled capsules which a) are water-insoluble or partly water-soluble, b) consist of water-swellable substances (powder, granulates or pills of, for example, calcium carboxy-methylcellulose or polyvinylpyrrolidone) and c) contain elements (tablets) with the active ingredient in the center of the capsule.
The prior art also describes sustained-release preparations using polymers. Thus EP-068446, for example, discloses the use of methylcellulose or carboxymethylcellulose in sustained-release mixtures.